Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), but not gluten, elicit modest symptoms of irritable bowel syndrome: a ...
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Downloaded from https://academic.oup.com/ajcn/article/115/2/344/6382986 by Uppsala University user on 14 March 2022
See corresponding editorial on page 327.
Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs),
but not gluten, elicit modest symptoms of irritable bowel syndrome:
a double-blind, placebo-controlled, randomized three-way crossover
trial
Elise Nordin,1 Carl Brunius,1 Rikard Landberg,1 and Per M Hellström2
1 Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; and 2 Department of Medical Sciences, Uppsala
University, Uppsala, Sweden
ABSTRACT warrant further detailed studies to identify possible underlying
Background: Irritable bowel syndrome (IBS) has been associated causes and enable individual prediction of responses. This trial was
with diets rich in fermentable oligo-, di-, monosaccharides, and registered at www.clinicaltrials.gov as NCT03653689. Am J Clin
polyols (FODMAPs), and gluten. Most previous studies have been Nutr 2022;115:344–352.
single-blind and have focused on the elimination of FODMAPs or
provocation with single FODMAPs. The effect of gluten is unclear, Keywords: diet, fermentation, functional gastrointestinal disorder,
large trials isolating the effect of gluten from that of FODMAPs are polyols, saccharides, irritable bowel syndrome, FODMAPs, gluten,
needed. double-blind, crossover trial
Objectives: The aims of this study were to ensure high intakes of
a wide range of FODMAPs, gluten, or placebo, and to evaluate the
Introduction
effects on IBS symptoms using the IBS-severity scoring system (IBS-
SSS). Irritable bowel syndrome (IBS) is a chronic functional bowel
Methods: The study was carried out with a double-blind, placebo- disorder affecting 3–5% of the population (1). It is characterized
controlled, randomized 3-way crossover design in a clinical facility by recurring abdominal pain over ≥3 mo within a 6-mo
in Uppsala from September 2018 to June 2019. In all, 110
participants fulfilling the IBS Rome IV criteria, with moderate to
The study was funded by Formas (grant number: 2016-00314) and the
severe IBS, were randomly assigned; 103 (90 female, 13 male)
Swedish Research Council (grant number: 2017-05840). The funders had no
completed the trial. Throughout, IBS participants maintained a diet part in the study design, collection, analysis, interpretation of data, writing,
with minimal FODMAP content and no gluten. Participants were or any other type of involvement.
block-randomly assigned to 1-wk interventions with FODMAPs Supplemental Tables 1–5 and Supplemental Methods 1 and 2 are available
(50 g/d), gluten (17.3 g/d), or placebo, separated by 1-wk washout. from the “Supplementary data” link in the online posting of the article and
All participants who completed ≥1 intervention were included in the from the same link in the online table of contents at https://academic.oup.
intention-to-treat analysis. com/ajcn/.
Results: In participants with IBS (n = 103), FODMAPs caused Address correspondence to EN (e-mail: elise.nordin@chalmers.se).
higher IBS-SSS scores (mean 240 [95% CI: 222, 257]) than placebo Abbreviations used: A, FODMAPs; B, gluten; C, placebo in
blocks of 12; FODMAPs, fermentable oligo-, di-, monosaccharides,
(198 [180, 215]; P = 0.00056) or gluten (208 [190, 226]; P = 0.013);
and polyols; IBS-C/D/M/U, irritable bowel syndrome-
no differences were found between the placebo and gluten groups
constipation/diarrhea/mixed/unsubtyped; IBS-SSS, irritable bowel
(P = 1.0). There were large interindividual differences in IBS-SSS syndrome-severity scoring system; ITT, intention-to-treat; PP, per-protocol;
scores associated with treatment. No adverse events were reported. SF-36v2, Short Form 36 version 2; QoL, quality of life.
Conclusion: In participants with IBS, FODMAPs had a modest Received July 9, 2021. Accepted for publication September 29, 2021.
effect on typical IBS symptoms, whereas gluten had no effect. The First published online October 7, 2021; doi: https://doi.org/10.1093/
large interindividual differences in responses to the interventions ajcn/nqab337.
344 Am J Clin Nutr 2022;115:344–352. Printed in USA. © The Author(s) 2021. Published by Oxford University Press on behalf of
the American Society for Nutrition. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original
work is properly cited. For commercial re-use, please contact journals.permissions@oup.comFODMAPs not gluten, elicit IBS symptoms 345
period, in association with altered bowel habits. IBS is subtyped with food lists based on the Monach University presentation of
based on the predominant stool pattern: constipation (IBS-C), FODMAP contents in various foods (26, 27), recipes, and an app
diarrhea (IBS-D), a mix of constipation and diarrhea (IBS-M), or (Belly Balance Sverige AB, Stockholm, Sweden) for verifying
unsubtyped (IBS-U) (2). The diagnosis is symptom based, using the FODMAP and gluten contents by scanning product labels.
the Rome IV criteria, currently with no biochemical diagnostic After a first run-in week with a low-impact diet, participants
markers (2). People with IBS experience lower quality of life were exposed to a single combined FODMAP/gluten challenge,
(QoL) than the general population (3). with blood samples drawn over the course of 4 h after the
Symptomatic treatment of IBS includes dietary adaptation, challenge. The purpose of this FODMAP/gluten challenge test
with a focus on prebiotics (4), probiotics (5), gluten (6), and fer- was to provide samples to be analyzed at a later time. On the
mentable oligo-, di-, monosaccharides and polyols (FODMAPs) following morning, a spot urine sample was collected, after which
(6, 7). FODMAPs are poorly absorbable carbohydrates that participants continued the low-impact diet for another week.
Downloaded from https://academic.oup.com/ajcn/article/115/2/344/6382986 by Uppsala University user on 14 March 2022
exert an osmotic load on the gut, and are rapidly fermented by Participants were then prompted to consume blinded food in the
colonic bacteria, resulting in gas production causing abdominal form of rice porridge with added FODMAPs, gluten, or placebo
distention, bloating, and pain (7). A low FODMAP diet has during weeks 3, 5, and 7, but no porridge during weeks 4 and 6
been shown to improve IBS symptoms (8–16) and is currently (Figure 1). Blood and feces samples were collected at visits at the
the dietary factor with most evidence as a regimen for IBS end of each study week (to be analyzed at a later time). Before
(6). However, many FODMAP restriction studies suffer from each visit, participants were fasted overnight and arrived in the
suboptimal design, being no or single-blind (8–15). In fact, early morning for investigations.
only 1 double-blind study with a low FODMAP diet has been
conducted and was carried out in children (16). Furthermore, Participants
most studies have focused on the elimination of FODMAPs Inclusion criteria of the study were: female and male
from the diet, rather than provocation (8–16). A few studies, all with moderate to severe IBS (IBS-SSS score >175) (28),
single-blind, have employed provocations using all FODMAP BMI 18.5–38 kg/m2 , age 18–70 y, hemoglobin 120–160 g/L,
components (12, 17), though similar double-blind studies have thyroid-stimulating hormone346 Nordin et al.
Combined (CBA) Gluten
FODMAP
and
a glute (ACB)
nd gluten Gluten
test (BAC) Gluten
Run-in Run-in Wash-out Wash-out
Week
e 1
Week Week
e 2
Week Week
e 3
Week W eek
Weeke 4 Week
e 5
Week Week
e 6
Week Week
e 7
Week
Low-impact diet B Blood drawn
U Urine collection
Visit 1 2 3 4 5 6 7
F Faecal collection
Biosampling BU BF BF BF BF BF BF
Q Questionnaires
Clinical QA QA QA QA QA QA QA A Anthropometric
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measurements
FIGURE 1 Study design with the 3 intervention sequences used. A, FODMAPs; B, gluten; C, placebo in blocks of 12; FODMAPs, fermentable oligo-,
di-, monosaccharides, and polyols.
to ensure sufficient statistical power to allow differentiation activity and alcohol consumption during the preceding 24 h
of a potential effect of sequencing.) was done by personnel and adherence to fasting routines overnight. Bodyweight, waist
with no involvement in the study. Randomization was carried circumference at the umbilicus level, and systolic and diastolic
out before the combined FODMAPs/gluten challenge. The blood pressure were measured after the participant had rested
randomization outcomes were delivered to the study site 1–3 d in supine position for ≥10 min. At each visit, the following
before participants were allocated to treatments. Two individuals questionnaires were filled out for the preceding study week: IBS-
were mistakenly assigned the sequence ABC. It did not affect SSS (28), Short Form 36 version 2 (SF-36v2) (30), stool diary,
the results. For clarity, the individuals are therefore presented study compliance form for the amount of porridge eaten during
as receiving their planned sequence (ACB/BAC). Unblinding the week, and notes on any deviations from the protocol due to
of data was done after database locking and completion of dietary changes, illness, or changes of medication.
the study, before the statistical analyses. For the participants, The IBS-SSS is a validated questionnaire used to estimate
there were no assessments of consumption order of the diets. the severity of IBS during a 10-d period by addressing severity
During product development by our research group, a panel of of abdominal pain, abdominal distension, dissatisfaction with
20 people evaluated the rice porridge produced, which could not bowel habits, and interference with QoL, on a 0–100 mm
be distinguished based on appearance, taste, or consistency. visual analogue scale. The item frequency of abdominal pain
is addressed as ordinal data on a scale ≤100 points (10 levels).
The total IBS-SSS score ranges between 0 and 500, with 300
The initial combined FODMAPs/gluten challenge consisted considered to represent severe IBS. The SF-36v2 measures health
of a cake containing FODMAPs (fructose 19.5 g, lactose and QoL over the last 7 d. The study period of the questionnaires
15.7 g, fructo-oligosaccharides 7 g, galacto-oligosaccharides was modified to reflect the preceding 5 d (the IBS-SSS item
1.5 g, sorbitol 4.5 g, and mannitol 1.8 g) or gluten (17.3 g), each frequency of abdominal pain was modified to multiply the
with cocoa for taste and 150 mL water (Supplementary Tables value by 20 instead of 10, in order to keep the scale to 100),
1 and 2). During the following intervention weeks, participants and fit the study interventions with minimal carry-over effect.
consumed 3 portions daily of rice porridge with high amounts Questions concerning headache, fatigue, joint pain, dizziness,
of FODMAPs or gluten, using placebo as a reference point. The skin rash, numbness, and vomiting were added to the SF-36v2
amount of FODMAPs and gluten in the combined challenge test questionnaire (scoring low 1 to high 5). The questions were
corresponded to the daily dose of FODMAPs or gluten provided added to monitor extraintestinal symptoms, commonly present in
during test weeks. Rice porridge was selected as the vehicle for participants with nonceliac gluten or wheat sensitivity (25). All
FODMAP, gluten, and placebo because of its neutral taste and questionnaires used in the trial are presented in Supplementary
palatability. The intervention foods were similar in sweetness Methods 1. The stool diary retrieved information on bowel
(added sucrose; Supplementary Tables 1 and 2) and consistency, movements as spontaneous, complete and spontaneous, or
to ensure accurate blinding. The porridge was delivered in portion requiring a rescue laxative (31), stool consistency (32), and
packs with an instruction to add 125 mL water and heat before pain during bowel movements (visual analogue scale 0–100).
intake. The FODMAP intake during the interventions was 50% Procedures for the collection of blood, urine, and feces samples
higher than that reported for an Australian population (15). are described in detail in Supplementary Methods 2. Adverse
Lactose and gluten intakes were 50% higher than estimates of events were monitored during the study and within 1 mo after the
the average Swedish population intake (29). last food intervention week.
Anthropometric measurements and questionnaires Statistical analyses
At screening, participant height was measured using a A sample size calculation, assuming a relevant difference in
wall-mounted stadiometer. At each visit, compliance with the total IBS-SSS (50 points) (28) with a power of 0.8, and 20%
following aspects was noted: avoidance of vigorous physical dropout rate, was performed posthoc using individual SD for theFODMAPs not gluten, elicit IBS symptoms 347
interventions (SD = 111.6) in the study. Under these conditions, (Table 2). No difference was observed between gluten and
the required number of participants was 64, with the level of placebo (P = 1.0). The IBS-SSS score was 40 [10] points
significance in a 2-sided test set to 0.05/3 (Bonferroni correction). higher during the FODMAP intervention compared with during
The primary analysis was performed as intention-to-treat (ITT), the preceding washout week (P = 0.0012), whereas the
including all participants who completed assessment of ≥1 corresponding values for the gluten and placebo interventions
intervention. As a secondary analysis, a per-protocol (PP) test was were 27 [10] (P = 0.11) and 10 [10] (P = 1.0). The IBS-SSS score
performed, using ≥80% self-reported intake of the intervention ratings were similar between placebo treatment and the washout
foods as cutoff. The effect of diet was analyzed through linear weeks of the interventions (P >0.98; Supplementary Table
mixed modeling in R, using the lme4 v 1.1–25 package, with 3). When comparing the separate interventions, no differences
intervention and period as fixed factors and study participant as were identified in the proportion of participants with an increase
the random factor. Overall effects were investigated using type of >50 points (FODMAPs 46%, gluten 37%, placebo 35%)
or >100 points (FODMAPs 26%, gluten 20%, placebo 22%)
Downloaded from https://academic.oup.com/ajcn/article/115/2/344/6382986 by Uppsala University user on 14 March 2022
III tests, and when significant, subsequent pairwise comparisons
were based on differences in least square means, both adjusted in IBS-SSS scores (Figure 3). When IBS-SSS scores were
with Bonferroni correction. Intervention × IBS subtype was itemized, abdominal distension scores were found to be higher
initially included as a fixed factor but later removed, as it with FODMAPs than with placebo (P 80%) had 7 d between visits at the FODMAPs and gluten on gastrointestinal symptoms in people
study site. For 6 participants, 1 washout week was extended to with IBS, compared with placebo. The study indicated an effect
10–21 d. of FODMAP, but not gluten, in participants with IBS compared
The IBS-SSS score was highest with the FODMAP in- with placebo.
tervention (mean [SEM] = 240 [9]) compared with placebo The higher total IBS-SSS scores with FODMAPs than with
(198 [ 9]; P = 0.00056) or gluten (208 [9]; P = 0.013) placebo or gluten were mainly driven by the features abdominal348 Nordin et al.
(n = 195)
(n = 85)
(n = 44)
(n = 41)
(n = 110)
(n = 37)
(n = 36)
(n = 37)
(n = 3)
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(n = 1), sequence CBA)
(n = 110) (n = 1), sequence
(n = 1), sequence ACB)
(n = 36) (n = 34) (n = 37)
n=1
n=1
n=2
n = 35 n = 33 n = 35
n = 35 n = 33 n = 35
n = 35 n = 33 n = 35
n = 103
FIGURE 2 Flow chart of participants by sequence and food intervention period. A, FODMAPs; B, gluten; C, placebo in blocks of 12; FODMAPs,
fermentable oligo-, di-, monosaccharides, and polyols.
pain and abdominal distension. This is in line with previous clinically significant difference can be assumed for a score >50
studies of IBS and FODMAPs (8, 10, 12–14, 17). The increase (28), which has been the customary interpretation of results.
in total IBS-SSS score was modest, as all interventions raised Several studies eliminating FODMAPs from the diet of subjects
the IBS-SSS scoreFODMAPs not gluten, elicit IBS symptoms 349
TABLE 1 Baseline characteristics by intervention sequence (CBA, ACB, BAC; A = FODMAPs, B = gluten, C = placebo)1 and in total. Data are presented
for the full analysis set
Baseline characteristics CBA (n = 35) ACB (n = 33) BAC (n = 35) Total (n = 103)
Female/male, n 26/9 32/1 32/3 90/13
Mean age, y ± SD 43 ± 17 44 ± 15 50 ± 13 46 ± 15
Mean BMI, kg/m2 ± SD 24 ± 3 23 ± 4 25 ± 4 24 ± 4
Dietary preference, %
Omnivorous diet 83 76 91 83
Vegetarian 17 18 9 15
Vegan 0 3 0 1
Dietary restrictions, %
Exclusion of gluten 37 42 49 43
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Exclusion of lactose 43 58 46 49
Other exclusions 34 55 57 49
No dietary exclusions 23 12 20 18
Mean blood pressure ± SD
Systolic, mmHg 123 ± 14 120 ± 12 128 ± 16 124 ± 14
Diastolic, mmHg 76 ± 8 74 ± 12 79 ± 9 76 ± 10
Mean waist circumference, cm ± SD 88 ± 11 88 ± 10 93 ± 11 90 ± 11
IBS severity at baseline
Total IBS-SSS >175–300, n 14 20 21 41
Total IBS-SSS >300, n 21 13 14 62
IBS subtype, n
Constipation 9 11 9 29
Diarrhea 17 7 11 35
Mixed 9 15 15 39
Mean total IBS-SSS ± SD
Week 2 222 ± 88 232 ± 69 178 ± 78 210 ± 82
Week 3 226 ± 88 241 ± 80 191 ± 96 218 ± 90
Week 4 183 ± 84 192 ± 87 158 ± 96 177 ± 90
Week 5 205 ± 90 197 ± 91 229 ± 93 210 ± 91
Week 6 209 ± 105 186 ± 88 148 ± 90 181 ± 97
Week 7 248 ± 94 230 ± 92 172 ± 86 216 ± 96
Mean total IBS-SSS at baseline ± SD
Total IBS-SSS score (0–500) 309 ± 48 309 ± 41 306 ± 61 308 ± 50
Severity of abdominal pain (0–100) 49 ± 17 54 ± 16 54 ± 18 52 ± 17
Frequency of abdominal pain (0–100) 64 ± 25 62 ± 22 59 ± 26 62 ± 24
Abdominal distension (0–100) 51 ± 24 56 ± 17 51 ± 23 52 ± 22
Dissatisfaction with bowel habits (0–100) 71 ± 19 65 ± 17 73 ± 20 70 ± 19
Interference with quality of life (0–100) 74 ± 12 72 ± 11 69 ± 11 72 ± 11
1 Two individuals were by mistake assigned the sequence ABC. It did not affect the results, for clarity, the individuals are therefore presented as receiving
their original sequence (ACB/BAC). A, FODMAPs; B, gluten; C, placebo in blocks of 12; FODMAPs, fermentable oligo-, di-, monosaccharides, and polyols;
IBS-SSS, irritable bowel syndrome-severity scoring system.
compared with either a sham or habitual diet (11, 12, 14, 19). Previous studies suggest that people without a diagnosis
However, the intervention effect in those studies was likely of celiac disease may be sensitive to gluten (25). However,
confounded with general treatment or placebo effects and the methodological issues such as differences in study design,
non- or single-blind design. Like us, Hustoft et al. (19) found inclusion criteria, gluten exposure level, and the presence of
that provocation with fructo-oligosaccharides increased IBS- other food components (e.g. FODMAPs [36], amylase trypsin
SSS scores only slightly. Skodje et al. (18) found symptoms inhibitors [36], and wheat lectin agglutinin [37]) make it difficult
only moderately increased by FODMAPs but not by gluten, to draw firm conclusions (36). To minimize such methodological
whereas Shepherd et al. (20), who included only subjects with issues, we exposed the participants to a high dose of a gluten
IBS with fructose malabsorption in their study, found profound fraction while actively excluding FODMAPs, but were unable
effects of provocation with fructose and/or fructan. The modest to obtain gluten free from amylase trypsin inhibitors and wheat
effects of the dietary challenges in our study do not rule out lectin agglutinin. Still, the levels of these components in our study
that some people experience strong responses to FODMAPs and are unknown.
gluten, since there were pronounced interindividual differences Several IBS studies employing a low FODMAP diet over
in response to the interventions. Future investigations should time have reported increased QoL (8, 10–12, 14). One study
evaluate the magnitude and causes of differential responses provoking with fructo-oligosaccharides found no effect on
among individuals and how such responses can be predicted QoL (19), whereas another study found negative effects on
(33–35). vitality (18). In our study, there were no differences between350 Nordin et al.
10 [11] (–11, 31)
Gluten-placebo
5 [3] (–1, 11)
5 [4] (3, 13)
1 Mixed linear models were used with intervention and period as fixed factors and participant as the random factor (total n = 103). Data are presented as mean [SEM] (95% CI). FODMAPs, fermentable
P = 0.74
P = 0.25
P = 1.0
FODMAPs-gluten
32 [11] (10, 54)
9 [4] (1, 17)
8 [3] (2, 14)
P = 0.013
P = 0.072
P = 0.023
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FODMAPs-placebo
42 [11] (20, 64)
14 [4] (6, 22)
13 [3] (7, 19)
P = 0.00056
P = 0.0020
P 50 points, or >100 points, for FODMAPs, gluten, and
1.0
placebo interventions compared with the respective washout periods. Data
were analyzed with McNemar’s test. FODMAPs, fermentable oligo-, di-,
monosaccharides, and polyols; IBS-SSS, irritable bowel syndrome-severity
198 [9] (180, 215)
scoring system.
32 [2] (27, 36)
32 [2] (28, 37)
44 [3] (37, 51)
50 [2] (46, 54)
52 [2] (47, 56)
Placebo
oligo-, di-, monosaccharides, and polyols; IBS-SSS, irritable bowel syndrome-severity scoring system.
the interventions regarding interference with the QoL item in
IBS-SSS or the secondary analysis of QoL. Concerning stool
consistency, previous studies found an effect connected to lower
FODMAP intake (9, 11, 14, 15), whereas others did not (10, 13).
Similar discrepancies are reported for stool frequency (9–11, 13,
208 [9] (190, 226)
34 [2] (29, 38)
37 [2] (33, 42)
52 [2] (48, 56)
50 [2] (46, 54)
49 [4] (42, 55)
14). As regards gluten, there are corresponding discrepancies in
Gluten
perceived stool habits (18, 22, 24, 38). In this study, no effect
on the consistency or frequency of stool was found for any
intervention and similar results were observed for bowel habit
dissatisfaction in IBS-SSS. Halmos et al. (39) found a large
discrepancy in subjective reporting and objective measures of
stool consistency and pointed out that patient-reported bowel
240 [9] (222, 257)
habits warrant further investigation.
56 [2] (52, 60)
35 [2] (31, 40)
45 [2] (40, 49)
55 [2] (51, 59)
58 [4] (51, 65)
FODMAPs
We found that the baseline IBS-SSS scores were higher than
those for washout weeks. This may be explained by a drastically
reduced FODMAP and gluten intake compared with participants’
habitual diets, increased participant awareness of dietary choices,
and more regular meal patterns. Another possibility is that
the lower IBS-SSS scores during the study may relate to the
psychological attention effect due to frequent visits to a health
Dissatisfaction with bowel habits
Interference with quality of life
care environment, which has previously been shown to improve
Frequency of abdominal pain
Severity of abdominal pain
health and feelings of well-being (40). Also, behavioral and diet
therapies have both been found to be important for the treatment
Abdominal distension
Total IBS-SSS score
of IBS (41).
A limitation of our interventions was the 7-d exposures, shorter
than the 10 d usually applied when using IBS-SSS. However,
previous studies have successfully conducted food challenges
from 2 to 7 d (17, 18). Furthermore, the low-impact diet was
not provided as ready-made meals, but as dietary advice to theFODMAPs not gluten, elicit IBS symptoms 351
participants to consume foods with a low likelihood to provoke the food products used in the study; EN and PH: recruited participants; PH:
IBS symptoms. However, the low IBS-SSS scores during all was the medical doctor responsible for the study; and all authors: read and
washout periods suggest high compliance with the low-impact approved the final manuscript. The authors report no conflicts of interest.
diet throughout the study. Moreover, compliance with the low-
impact diet was based on self-reporting, which is one of the main
hurdles in nutrition research. There are no validated compliance Data Availability
biomarkers reflecting FODMAP or gluten intake. There was Data described in the manuscript, code book, and analytical
unfortunately no monitoring of the advised low-impact diet code will be made available upon request. For data to be shared, a
during the trial, but participants were provided extensive support written request must be sent including a data analysis plan which
to ensure compliance with a low-impact background diet. Also, needs to be approved by the authors. Before data are shared a
sweetening of the diet with sucrose can be questioned, due data access agreement must be concluded. Only deidentified data
Downloaded from https://academic.oup.com/ajcn/article/115/2/344/6382986 by Uppsala University user on 14 March 2022
to reported mutations in the sucrase-isomaltase gene in IBS can be shared. In order to access data, contact the corresponding
(42). These genetic variants are rare, so major bias is excluded, author at elise.nordin@chalmers.se.
as confirmed by the similarity between placebo and washout
weeks. Inclusion of lactose in the FODMAP intervention may
be questioned, but 89% of participants were of Swedish descent,
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